Type 4 Pritelivir Crystal Form for Stability and Solubility
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Solution Overview
Problem
Current treatments for herpes simplex virus (HSV) infections, such as nucleoside analogues, are inadequate in preventing recurrent outbreaks and addressing viral shedding, and existing forms of pritelivir lack stability and solubility for effective drug delivery.
Innovation Solution
A novel crystalline form of pritelivir, designated as Type 4, which is a sesqui-hydrated form characterized by specific XRPD peaks and DSC thermogram features, offering improved stability and solubility for effective treatment of HSV infections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms of pritelivir are used, then the drug can be administered, but the stability and solubility are insufficient for effective treatment
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing a new crystalline form (Type 4) of pritelivir with specific XRPD peaks at 12.1, 14.6, and 18.3° 2θ and DSC onset temperatures at 60, 108, and 185°C. This new crystalline form exhibits improved stability across varying humidity levels and enhanced solubility in aqueous media compared to previous forms, directly resolving the contradiction between stability and solubility through modification of the physical state parameters of the drug substance.
2Reliability
If nucleoside analogues are administered at very high doses, then antiviral effect is achieved, but safety concerns and mutagenicity arise
Solution Approach 1:
The patent introduces an intermediary mechanism by using pritelivir, a helicase-primase inhibitor, which operates through a different molecular target than traditional nucleoside analogues. Instead of requiring phosphorylation by viral thymidine kinase and inhibiting DNA polymerase like nucleoside analogues, pritelivir directly inhibits the viral heterotrimeric complex of helicase, primase, and cofactor subunits. This intermediary approach to viral replication inhibition eliminates the mutagenic effects associated with high-dose nucleoside analogue incorporation into host DNA while maintaining antiviral efficacy.
3Reliability
If nucleoside analogues are used to treat HSV, then some antiviral activity is achieved, but they are ineffective against TK-deficient viruses
Solution Approach 1:
The patent applies inversion by reversing the mechanism of action from nucleoside analogue-based inhibition to direct helicase-primase inhibition. Traditional nucleoside analogues require viral thymidine kinase to phosphorylate them as an activation step, creating vulnerability to TK-deficient resistant strains. Pritelivir inverts this approach by directly binding to and inhibiting the helicase-primase complex without requiring prior phosphorylation, thereby overcoming resistance mechanisms that affect nucleoside analogues and expanding adaptability to resistant viral strains.
Data Source
AI summary
The invention relates to a novel crystalline form of pritelivir, as well as to pharmaceutical compositions comprising the same, and to methods for its production and use of the crystalline form in a medicament and for the treatment of herpes virus.